ASYMMETRIC SYNTHESIS OF IONOPHORE/MACROLIDE ANTIBIOTICS

这项拟议研究的目标是对具有临床显著生物活性的天然存在物质的全合成做出创造性贡献。这笔拨款将继续用于发展新的立体选择反应，并将这种方法应用于聚酮类抗生素和抗肿瘤药物的不对称合成。合成目标将包括黄芪抑素A、两苯二酚3、果皮毒素、石蒜苷A、耳蜗霉素和己基临床酸。在本研究项目中开发的对映选择性过程已被整合到拟议的目标结构的合成计划中。处理反应发现的方法学研究将强调反应的发展，以控制和最终预测复杂醛醇过程的立体化学过程。这些研究的持续目标是揭示一些预测复杂醛醇片段偶联反应立体化学结果的一般规则。与多核苷酸、多肽和多糖一起，多酮类化合物代表了由共同亚基组装而成的第四大类天然物质。在通过复杂的醛醇加成反应组装的天然材料家族中，扩展比酰胺结构类比更大的挑战。我们的长期目标是开发所有必要的工具，以有效地组装复杂的聚丙酸酯和聚醋酸酯目标。不对称催化作用已被用于手性构建单元的构建。手性烯醇酸酯方法已被用于立体调节醛醇过程，双立体分化醛醇反应的研究揭示了如何提高这些片段偶联反应的设计可预测性。我们的目标是建立快速组装任何聚酮靶结构所需的所有反应。

The objectives of this proposed research are to make creative contributions to the total synthesis of naturally occurring substances possessing clinically significant biological activity. This grant will continue to address the development of new stereoselective reactions and the application of this methodology to the asymmetric synthesis of polyketide-derived antibiotics and anti-neoplastic agents. The synthesis targets will include aflastatin A, amphidinol 3, pectenotoxin, callipeltoside A, cochleamycin, and hexacyclinic acid. Enantioselective processes developed within this research program have been integrated into the proposed synthesis plans for the indicated target structures. The methodological studies dealing with reaction discovery will emphasize the development of reactions for controlling and ultimately predicting the stereochemical course of complex aldol processes. The ongoing goal of these studies has been to reveal some of the general rules for predicting the stereochemical outcome of complex aldol fragment coupling reactions. Along with polynucleotides, peptides and polysaccharides, polyketides represent the fourth broad family of naturally occurring materials that are assembled from common subunits. In extending the family of naturally occurring materials that are assembled through complex aldol addition reactions is a far greater challenge than the amide construction analogy. Our long-term objective has been the development all of the necessary tools for the efficient assemblage of complex polypropionate and polyacetate targets. Asymmetric catalysis has been directed to the construction of chiral building blocks. Chiral enolate methodology has been developed for stereoregulated aldol processes, and studies on double stereodifferentiating aldol reactions have revealed how to improve the design predictability of these fragment coupling reactions. Our goal has been to set in place all of the reactions necessary for the rapid assemblage of any polyketide target structure.